Two new prototype microbicide products will be developed: one based on an intravaginal ring delivery system and one on a bioresponsive (smart) gel delivery vehicle. Both products will be designed to function with the following attributes: (1) extended residence in the vagina such that their use is not coitally dependent;(2) embody either single or combination anti-HIV microbicides;and (3) have favorable acceptability by women. The smart gel will spread well initially upon insertion, and then increase in physical integrity and remain in place for at least 24 hours. The intravaginal ring will deliver a constant dose of microbicide molecules continuously over a duration of one month or greater. Three new families of active ingredients will be developed and delivered by the new vehicles. These molecules target multiple steps in the HIV infection and replication pathway and include the dual acting pyrimidinediones (inhibit virus entry and reverse transcription), ISIS 5320 (inhibits CD4-gp120 mediated attachment) and the virus inactivating NCp7 inhibitors. Collectively, these active ingredients target both cell-free and cell-associated virus. Optimal formulation strategies employing either gels or rings will be designed and implemented. The proposed work scope integrates new basic science and technology, preclinical development and exploratory clinical development. The candidate novel microbicides will be optimized for activity, stability and potency against both wild type and drug-resistant viruses. Medicinal chemistry will continue to provide compounds with enhanced antiviral properties in single or combination products. The new microbicide science and technology will fill critical gaps in the field, and foster new delivery systems that are optimized with respect to vaginal deployment and drug delivery functions. Simultaneously, current knowledge and evaluation methods for acceptability of gels and rings will be expanded, and physical attributes of these vehicles will be designed to co-optimize both behavioral acceptability and biological functionality. Product development will progress in synchrony with the new scientific understanding of HIV neutralization mechanisms, delivery system biomaterials and functionality, microbicide product pharmacokinetics and pharmacodynamics, and human perception and acceptability. The set of novel new experimental methods and pharmacokinetic and pharmacodynamic models is intended to be translatable for widespread use in the microbicide pipeline. PROJECT 1: Delivery Systems for Long Acting Combination Microbicides Kiser, P Description (provided by applicant): Those who desire to develop a safe and effective microbicide continue to look toward drug delivery to provide solutions to patient compliance, drug stability and achieving effective pharmacokinetics of the multiple active agents over an acceptable duration. This proposal describes the development and testing of two new long acting vaginal drug delivery systems for the prevention of HIV in women: a thermoplastic intravaginal ring and new smart vaginal gels. We will evaluate three classes of compounds that inhibit HIV-1 1) dual reverse transcriptase/entry inhibitors (pyrimidinediones), 2) viral nucleocapsid protein Zn finger inhibitors (S-acyl- mercaptobenzamide thioesters) and 3) a potent V3 loop inhibitor (G-quartet phosphothiolate backbone oligonucleotide 5TTGGGGTT3'). In specific aim 1, these compounds will subject to preformulation screening of solubility and stability alone and together. Lead members of each class will be selected based on stability and appropriateness of the compound for each drug delivery system. In specific aim 2, selected leads will be formulated in dual intravaginal ring segments made by extrusion of thermoplastic elements containing solubilized or dispersed antiviral agents. Release rate will be measured as a function of loading and ring composition. We will also optimize the mechanical properties and dimensions of the intravaginal ring to match vaginal ring products currently on the market. Based on stability and antiviral activity and toxicity results we will select two compounds from the series above and coformulate them in conjoined dual segment rings that co-deliver two antiviral agents simultaneously at concentrations customized to their pharmacokinetics and pharmacodynamics. Finally in specific aim 3, we will develop the first non-temperature sensitive smart microbicide gel out of FDA approved materials whose properties allow it to be applied at a relatively low viscosity and whose durability and duration in the vaginal lumen would increase soon after application to provide a durable and 24 hour duration gel. Two different antiviral agents from above will be formulated in these gels again based on stability, toxicity and antiviral activity collected in specific aim 1. Project 1 and 2 will interact intensely in the optimization of the gels and in the development of the pharmacokinetic models that will guide the design of the drug delivery systems. Project 3 will provide design criteria for the gels and rings from human acceptability studies.